Citations

Abstract The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5–6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.

Abstract Objective To evaluate the association between hypovitaminosis D and outcomes of symptom severity, mood disorders, fatigue, and quality of life in fibromyalgia (FM) patients. Methods Five hundred ninety-three FM patients were surveyed from May 2012 to November 2013. Patients with serum vitamin D <25 ng/mL were considered to have hypovitaminosis D. The primary outcome was FM symptom severity (FIQ-R questionnaire). Secondary outcomes included quality of life (SF-36), fatigue (MFI-20), anxiety (GAD-7), and depression (PHQ-9). Independent t tests and chi-square tests were performed for continuous and categorical variables, respectively. Regression analysis was performed adjusting for age, gender, body mass index, ethnicity, and season. A post hoc analysis examined for correlation between outcomes and serum vitamin D (ng/mL) as a continuous variable. Results One hundred twenty-two patients (20.6%) had hypovitaminosis D. In our adjusted regression analysis, the total FIQ-R score in patients with hypovitaminosis D was higher compared with control patients with adequate serum vitamin D (57.85 ± 18.09 vs 62.79 ± 18.10, P = 0.04). Adjusted regression analysis revealed higher total GAD-7 (P = 0.01) and higher total PHQ-9 scores (P = 0.04) in patients with hypovitaminosis D compared with control patients. There were no differences based on severity of depression or anxiety. No differences in fatigue or quality of life were identified. Unadjusted post hoc analysis revealed that as serum vitamin D increased, there was an association with lower total FIQ-R (β coefficient = –0.11, P = 0.02) and lower SF-36 subscale scores of role-physical (β coefficient = –0.10, P = 0.03). Adjusted post hoc analysis revealed no significant associations. Conclusions Hypovitaminosis D may be a risk factor for worse symptom severity, anxiety, and depression in FM patients.

Background: With increasing demand for neurologists, nontraditional health care delivery mechanisms have been developed to leverage this limited resource. Introduction: Telemedicine has emerged as an effective digital solution. Over the past three decades, telemedicine use has steadily grown; however, neurologists often learn on the job, rather than as part of their medical training. The current literature regarding telestroke training during neurology training is sparse, focusing on cerebrovascular fellowship curricula. We sought to enhance telestroke training in our neurology residency by incorporating real-life application. Materials and Methods: We implemented a formal educational model for neurology residents to use telemedicine for remote acquisition of the National Institutes of Health Stroke Scale (NIHSS) for patients with suspected acute ischemic stroke (AIS) before arrival at our comprehensive stroke center. This three-phase educational model involved multidisciplinary classroom didactics, simulation exercises, and real-world experience. Training and feedback were provided by neurologists experienced in telemedicine. Results: All residents completed formal training in telemedicine prehospital NIHSS acquisition and had the opportunity to participate in additional simulation exercises. Currently, residents are gaining additional experience by performing prehospital NIHSS acquisition for patients in whom AIS is suspected. Our preliminary data indicate that resident video encounters average 10.6 min in duration, thus saving time once patients arrive at our hospital. Discussion: To our knowledge, this is the first report of a telestroke-integrated neurology residency program in a comprehensive stroke center resulting in shortened time to treatment in patients with suspected AIS. Conclusions: We present a model that can be adopted by other neurology residency programs as it provides real-world telemedicine training critical to future neurologists.

Background: Physiological alterations during the perianesthetic period may contribute to secondary neurocognitive injury after a concussion. Methods: Patients exposed to concussion and who received an anesthetic within 90 days were matched to unexposed patients without concussion. Intraoperative and postoperative events were compared. Subgroup analyses assessed relationships among patients with a concussion in the prior 30, 31 to 60, and 61 to 90 days and their respective unexposed matches. To facilitate identification of potential targets for further investigation, statistical comparisons are reported before, as well as after, correction for multiple comparisons. Results: Sixty concussion patients were matched to 176 unexposed patients. Before correction, 28.3% postconcussion versus 14.8% unexposed patients reported postanesthesia care unit pain score≥7 (P=0.02); 16.7% concussion versus 6.5% unexposed patients reported headache within 90 days of anesthesia (P=0.02) and 23.5% of patients who received surgery and anesthesia within 30 days of concussion experienced headache within 90 days of anesthesia compared with 7.1% in the unexposed group (P=0.01). Patients who experienced concussion and had anesthesia between 31 and 60 days after injury had a postanesthesia care unit Richmond Agitation and Sedation Scale score of −1.61±1.29 versus a score of −0.2±0.45 in unexposed patients (P=0.002). After adjusting the P-value threshold for multiple comparisons, the P-value for significance was instead 0.0016 for the overall cohort. Our study revealed no significant associations with application of adjusted significance thresholds. Conclusions: There were no differences in intraoperative and postoperative outcomes in patients with recent concussion compared with unexposed patients. Before correction for multiple comparisons, several potential targets for further investigation are identified. Well-powered studies are warranted.

Abstract Abstract 3101 The POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) syndrome is a rare paraneoplastic disorder secondary to a clonal plasma cell process. The most experience with successful outcomes in POEMS with disseminated disease has been with high dose chemotherapy followed by autologous stem cell transplantation (ASCT). However, the risk of relapse of POEMS following an ASCT or the outcome of the patients who relapse is not known. We therefore performed a retrospective review of POEMS patients who underwent ASCT at our center and subsequently relapsed or progressed. Over the past 12 years, 58 patients with POEMS underwent autologous stem cell transplantation at the Mayo Clinic, Rochester between Mar 18, 1999 and Jun 22, 2011. With a median follow up of 40 months (1–147 months), 12 patients have relapsed. The median time to relapse was 41 months. The 1, 2, and 5 year PFS rates were 98%, 94%, and 75%, respectively (Figure 1), and the 1, 2, and 5 year OS rates were 98%, 98%, and 94%. Of the 12 patients with documented relapse, 7 had baseline PET/CT scans all of which had FDG avid lesions. By 1 year, the FDG avidity had not resolved in 4 of these patients who then went on to either develop additional lesions or increasing SUV of existing lesions. Of the 12 patients with documented relapse, 8 had baseline VEGF measurements, and all but 1 had normalization by 1 year. The first sign of relapse was a clinical deterioration in 2, a rising M-protein in 3, and a rising plasma VEGF level in 5 patients. All of these patients had new or worsening of existing lesions on PET/CT scan (n= 9) or x-ray imaging (n= 3). The symptoms of clinical relapse included pain at the site of the lytic lesion and generalized pain with swelling. Of the patients who relapsed, 5 were treated with radiation therapy, 4 received lenalidomide or thalidomide, 2 had alkylator based therapy and 1 had bortezomib based therapy. One patient was treated with surgical resection of his hepatic plasmacytoma and 2 patients have been observed without needing definitive treatment as of yet. One patient also received anti-VEGF treatment with bevacizumab unsuccessfully after failing cyclophosphamide therapy. In this large cohort of POEMS patients treated with high dose chemotherapy and autologous stem cell transplantation in a single center, a relapse rate of 21% was noted. Not every patient who relapsed has been deemed to need further treatment, and most patients could be salvaged with chemotherapy or radiation. Only one patient died from relapsed POEMS following stem cell transplantation. Disclosures: No relevant conflicts of interest to declare.

Abstract The amyloidoses are heterogeneous diseases associated with the deposition of insoluble proteins or peptides with a characteristic beta-diffraction pattern extracellularly. At the current time, over 27 different extracellular fibril proteins are known to cause disease in humans. Iatrogenic amyloidosis is a rare, often not sought diagnosis. On occasion, patients with drug induced amyloidosis can present with other systemic features reminiscent of systemic immunoglobulin-derived (AL) amyloidosis, and may present a diagnostic challenge. Treatment of the latter often involves chemotherapy and/or stem cell transplantation, while the former tends to remain localized and needs local therapy; thus accurate diagnosis is critical. To this end, proteomic analysis of amyloid tissue has proven to be an invaluable tool in amyloid typing. We have analyzed the biochemical composition of iatrogenic amyloid using laser capture/tandem mass spectrometry (LC-MS/MS)-based proteomic analysis in 52 cases of insulin and enfuvirtide (Fuzeon¨) associated amyloidosis. In brief, 10-μm-thick sections of formalin-fixed paraffin-embedded tissues were stained with Congo red. Congo red positively staining tissue as viewed with a fluorescent light source appeared bright red. Positive areas were dissected using laser microdissection to a volume of at least 60,000 μm2; three microdissections were analyzed for each case. The microdissected material was collected into 0.5-ml microcentrifuge tube caps containing 35 μL Tris/EDTA/0.002% Zwittergent buffer. Microdissected fragments were subjected to a heat-mediated antigen retrieval method (98C for 90minutes) before being denatured via sonication and subsequently digested into tryptic peptides overnight using 0.5ug of trypsin. The resulting digests were then analyzed with nanoflow LC-MS/MS. The MS/MS spectra of each case were matched against a composite protein sequence database using three different search algorithms (Sequest, X!Tandem, and Mascot). The composite database contained the human SwissProt entries but was also augmented with known immunoglobulin variant domains, known amyloidogenic mutations from literature, the enfuvirtide amino acid sequence, and common contaminants. Reversed protein sequences were appended to the database for estimating the false discovery rates of the identifications. The peptide identification results were filtered using Scaffold software (Proteome Software, Portland, OR) and then filtered peptides were assembled into protein identifications. Candidate proteins with at least one high-confident (probability of identification >90%) unique peptide identification and at least four MS/MS spectral matches were considered for clinical interpretation. For each case, we created a personalized proteomic profile that lists all the confident protein identifications in each of the microdissection along with their respective MS/MS spectral counts. The number of MS/MS spectra matching to a protein is considered as a semi-quantitative measure of its abundance. The most abundant amyloidogenic protein detected across all microdissections and as interpreted in the context of the clinical history is considered to be the amyloid subtype. Figure 1 shows the results of insulin amyloidosis. Figure 2 shows the results of enfuvirtide amyloidosis. Amyloid deposits are shown to be composed of the recombinant drug in addition to amyloid precursor proteins such as apolipoprotein A-I, A-IV, E and serum amyloid P (SAP).Figure 1. Insulin-associated amyloidosisFigure 1. Insulin-associated amyloidosisFigure 2Enfuvirtide (Fuzeon¨)-associated amyloidosisFigure 2. Enfuvirtide (Fuzeon¨)-associated amyloidosis In conclusion, we show the biochemical composition of all known drug-induced iatrogenic amyloidosis and provide the utility of proteomic analysis in elucidating amyloid subtyping for accurate diagnosis and management. Legend: A spectral count number of greater than 4 is significant. The green boxes denote protein identification at a probability of over 95%, and yellow 80-94%. In figure 1, insulin (# 2) and in figure 2, enfuvirtide (#5) are shown in abundance, additionally other amyloid precursors such as apolipoproteins A-IV, E, A-I and SAP are also seen. Disclosures: No relevant conflicts of interest to declare.